Ligands of the estrogen receptor (ER) have been shown to inhibit inflammatory gene expression that typically causes a reduction of cytokines, chemokines, adhesion molecules and other inflammatory enzymes. Accordingly, ER ligands can provide a means to treat inflammation such as the inflammatory component of diseases including, for example, atherosclerosis, myocardial infarction (MI), congestive heart failure (CHF), inflammatory bowel disease and arthritis. Other potential therapeutic indications for these type of molecules include type II diabetes (Cefalu, J Womens Health & Gender-based Med., 2001, 10, 241; Yuan et al., Science, 2001, 293, 1673), osteoarthritis (Pelletier et al., Arthr. & Rheum., 2001, 44:1237; Felson et al., Curr Opinion Rheum, 1998, 10, 269) asthma (Chin-Chi Lin et.al., Immunol. Lett., 2000, 73, 57), Alzheimer's disease (Roth, A. et. al., J. Neurosci. Res., 1999, 57, 399) and autoimmune diseases such as multiple sclerosis and rheumatoid arthritis.
A common component of chronic inflammatory conditions is polymorphonuclear leukocyte and monocyte infiltration into the site of damage through increased expression of cytokines and adhesion molecules responsible for their recruitment. Overproduction of the cytokine interleukin (IL-6) has been associated with states of chronic inflammation (Bauer M. A. and Herrmann F., Ann. Hematol., 1991, 62, 203). Synthesis of the IL-6 gene is induced by the transcription factor, nuclear factor κB (NF-κB). Interference at this step in the inflammatory process can effectively regulate the uncontrolled proliferative process that occurs in these chronic conditions.
In endothelial cells, 17β-estradiol (E2) inhibits IL-1β induced NF-κB reporter activity and IL-6 expression in an ER dependent fashion (Kurebayashi S. et. al., J. Steroid Biochem. Molec. Biol., 1997, 60, 11). This activity correlates with anti-inflammatory action of E2 in vivo as confirmed in different animal models of inflammation. In models of atherosclerosis, E2 was shown to protect endothelial cell integrity and function and to reduce leukocyte adhesion and intimal accumulation (Adams, M. R. et al., Arterio., 1990, 1051; Sullivan, T. R. et al. J. Clin. Invst., 1995, 96, 2482; Nathan, L. et. al., Circ. Res., 1999, 85, 377). Similar effects of estrogen on the vascular wall also have been demonstrated in animal models of myocardial infarction (Delyani, J. A. et al., J. Molec. Cell. Cardiol., 1996, 28, 1001) and congestive heart failure. Clinically, estrogen replacement therapy (ERT) has been demonstrated to reduce the risk of mortality in patients with both CHF (Reis et. al., J. Am. Coll. Cardio., 2000, 36, 529) and MI (Grodstein, F. et. al., Ann. Int. Med., 2000, 133, 933; Alexander et. al., J. Am. Coll. Cardio., 2001, 38, 1; Grodstein F. et. al., Ann. Int. Med, 2001, 135,1). In ERT, clinical studies demonstrated an influence of E2 on the decrease in the production of β-amyloid 1-42 (Aβ42), a peptide central for the formation of senile plaques in Alzheimer's disease (Schonknecht, P. et. al., Neurosci. Lett., 2001, 307, 122).
3-(1-Naphthyl)-3-phenyl-2-cyanopropanoic acid amides have been shown to activate certain ER pathways and have anti-inflammatory activity as described in, for example, U.S. patent application Ser. No. 10/833,678, filed Apr. 28, 2004, incorporated herein by reference in its entirety. These compounds are useful in treating numerous diseases and disorders characterized as having, for example, an inflammatory component. Thus, new and improved methods for the preparation of these compounds are needed. The processes and intermediates provided herein can help meet these and other needs.